Data from VEGFR-1 Expressed by Malignant Melanoma-Initiating Cells Is Required for Tumor Growth

Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5⁺ melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31⁻ vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5⁺ MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5⁺ tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5⁺ subpopulations that constitutively expressed VEGFR-1 but not in ABCB5⁻ bulk populations that were predominantly VEGFR-1⁻. In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5⁺ VM morphology and inhibited ABCB5⁺ VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by >90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. Cancer Res; 71(4); 1474–85. ©2011 AACR.